Investigation of factors influencing radioiodine (I-131) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach

Radioiodine (I-131) therapy is the common treatment option for benign thyroid diseases. The objective of this study was to characterize I-131 biokinetics in patients with benign thyroid disease and to investigate and quantify the influence of patients' demographic and clinical characteristics on intra-thyroidal I-131 kinetics by developing a population model. Population pharmacokinetic analysis was performed using a nonlinear mixed effects approach. Data sets of 345 adult patients with benign thyroid disease, retrospectively collected from patients' medical records, were evaluated in the analysis. The two-compartment model of I-131 biokinetics representing the blood compartment and thyroid gland was used as the structural model. Results of the study indicate that the rate constant of the uptake of I-131 into the thyroid (k (tu)) is significantly influenced by clinical diagnosis, age, functional thyroid volume, free thyroxine in plasma (fT(4)), use of anti-thyroid drugs, and time of discontinuation of therapy before administration of the radioiodine (THDT), while the effective half-life of I-131 is affected by the age of the patients. Inclusion of the covariates in the base model resulted in a decrease of the between subject variability for k (tu) from 91 (3.9) to 53.9 (4.5)%. This is the first population model that accounts for the influence of fT(4) and THDT on radioiodine kinetics. The model could be used for further investigations into the correlation between thyroidal exposure to I-131 and the outcome of radioiodine therapy of benign thyroid disease as well as the development of dosing recommendations

The influence of biologically effective dose (BED) on the 131I therapy response in patients with benign thyroid disease – nonlinear mixed effect modelling approach

Aim. The purpose of the study was to explore the influence of biologically effective dose (BED [Gy]), the administered radioactivity dose (Aa [MBq]), the total absorbed dose (ABD [Gy]), the maximum of absorbed dose-rate (MXR [Gy/h]) to radioactive iodine (131I) on the response in patients with benign thyroid disease. Materials and methods. Data from adult patients with benign thyroid disease who had previously received a test dose of 131I activity were included in the analysis. Individual thyroid exposure parameters were estimated from the population biokinetic 131I model and the therapeutic activity doses (in range from 185 to 1300 MBq). Patients response was followed up at periodic intervals, starting from 4-6 weeks, up to one year after the administration of 131I. A successful clinical outcome was resolution of of hyperthyroidism. A population exposure-response analysis was performed using nonlinear mixed-effects modelling using NONMEM® (v. 7.4). The response data was modelled as ordered categorical with three levels (hyper-, eu- and hypothyroidism). The performance of the final model was evaluated using visual predictive check (VPC). Results. In total 95 adult patients were analyzed, including 57 (60%) with Graves’ disease, 22 (23.2%) with toxic multinodular goiter and 16 (16.8%) with toxic adenoma. The probability of the outcome was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. Among all tested exposure measures, BED was included in the final model. Its inclusion in the base model was statistically significant (p<0.001). The value of 289.7 Gy was associated with 80% probability of successful treatment outcome one year after 131I application in patients with median thyroid volume of 32.28 mL. Conclusion. The results indicate that using BED formalism could lead to a better individualisation of the therapy. The larger thyroid volume is associated with a lower probability of a successful outcome. References. Topic Vucenovic V, Rajkovaca Z, Jelic D, Stanimirovic D, Vuleta G, Miljkovic B, Vucicevic K. Investigation of factors influencing radioiodine ((131)I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach. Eur J Clin Pharmacol. 2018;74(8):1037-1045. European Commission. Council Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (2014). Official Journal of the European Union L13/2014 57:1-73. doi:10.3000/19770677.L_2014.013.eng Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016;26(10):1343-1421.PAGANZ, Sydney 2021 Virtual Meeting: 27th-29th Januar

Population exposure-response model of 131I in patients with benign thyroid disease

Purpose: The study aimed to explore the relationship of different exposure measures with 131I therapy response in patients with benign thyroid disease, estimate the variability in the response, investigate possible covariates, and discuss dosing implications of the results. Methods: A population exposure-response analysis was performed using nonlinear mixed-effects modelling. Data from 95 adult patients with benign thyroid disease were analysed. Evaluated exposure parameters were: administered radioactivity dose (Aa) [MBq], total absorbed dose (ABD) [Gy], maximum of absorbed dose-rate (MXR) [Gy/h] and biologically effective dose (BED) [Gy]. The response was modelled as ordered categorical data: hyper-, eu- and hypothyroidism. The final model performance was evaluated by a visual predictive check. Results: The probability of the outcome following 131I therapy was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. All exposure measures were statistically significant with p<0.001, with BED and ABD being statistically better than the other two. Nevertheless, as BED resulted in the lowest AIC value, it was included in the final model. Accordingly, BED value of 289.7 Gy is associated with 80% probability of successful treatment outcome 12 months after 131I application in patients with median thyroid volume (32.28 mL). The target thyroid volume was a statistically significant covariate. The visual predictive check of the final model showed good model performance. Conclusion: Our results imply that BED formalism could aid in therapy individualisation. The larger thyroid volume is associated with a lower probability of a successful outcome